Anthracyclines form one of the largest families of naturally occurring bioactive compounds. Several members of this family have shown to be clinically effective anti-neoplastic agents. These include, for example, daunorubicin, doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, aclarubicin, and caminomycin. For instance, these compounds have shown to be useful in the treatment of breast carcinoma, acute lymphocytic and non-lymphocytic leukemia, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, and other solid cancerous tumors.
However, in many cases, the problem of a transmembrane transport, or a transport across the blood-brain barrier, is of a paramount significance in improving bioavailability of a drug. The search for new anthracycline derivatives, especially for such substances that easily cross the blood-brain barrier, continues to this day. Such properties will allow widening anthracycline indications to include both primary and metastatic tumors of the central nervous system. These are some of the reasons why there is a continuously heightened interest in a synthesis of novel anthracycline antibiotics with variable lipophilicity, such as that described in U.S. Pat. Nos. 5,625,043 and 6,673,907. A change in lipophilic property may be achieved by modification of the glycoside moiety of the molecule; in particular, by alkylation of 3′-N and/or 4′-O atoms of the sugar.
In the method disclosed in U.S. Pat. No. 6,673,907, a number of compounds substituted at 3′-N are derived by direct alkylation of anthracyclines in DMF with benzylbromides. Substitution of anthracyclines at 4′-O position by aralkyl groups (substituted benzyl radicals) has traditionally been thought of as significantly less accessible. Such synthesis is complicated by the following difficulties:
(a) functional groups of both aglycone and sugar must be protected by the protection groups;
(b) production of 3′-azido-glycoside moiety is complicated by creation of equatorial and axial isomers, which further must be separated by stereospecific hydrolysis;
(c) the coupling step requires utilization of a minimum double excess amount of a sugar synthon that is produced, in its turn, in 5-6 synthetic stages. Coupling reaction completes with less than 100% stereospecificity, resulting in a creation of an undesirable stereoisomer that must be further removed;
(d) a total number of synthetic stages and chromatographic purification steps is greater than 10, precluding high yield of the desired product.
Current views on the relative reactive strength of nucleophilic groups place them in the following order: NH2≧aromatic OH≧aliphatic OH, and exclude the possibility of selective alkylation of aliphatic OH on a background of unprotected NH2 or aromatic OH. This results in the complicated method of synthesis of anthracycline derivatives substituted at 4′-O position as discussed above.
Benzylation of a sugar at the 4′ position in daunorubicin or its analogs by utilizing generally accepted benzylating agents such as benzyl halides+NaH; +BuLi; +t-BuOK, is impossible, because of direct preferential benzylation of nitrogen in the absence of the protective group at 3′-NH2 or a generation of the reaction center at the 3′-N Prot nitrogen. In addition, benzylation of a sugar at the 4′ position hinders removal of the protection group from the 3′-NH group.
The combination of these factors leads to reactions carried out simultaneously in several pathways, resulting in a poorly separable mixture of multiple products.
Previously, well-accepted methods of alkylation of 4′ hydroxyl group of sugar utilized 3,4-di-O-Acetyl-Rhamnal as a starting material. It was first converted to 3-azide (racemate); then, the desired optical isomer was separated and benzylated with BnBr in the presence of NaH. The synthon created by such method was then coupled to an independently-synthesized aglycone. Further modifications and removal of the protection groups yielded the desired final product.
Simplification in production of this class of compounds by modification of the microbiologically produced anthracycline precursors without separation of aglycone and sugar confers a great advantage to such process. For example, one such approach to the synthesis of idarubicin is described in U.S. Pat. No. 7,053,191. The process described in U.S. Pat. No. 7,053,191 decreases the number of synthetic stages from 11 or 12 to just 5.
A method of modifying the 3′-NH2 to 3′-N3 group in a glycoside part of the anthracycline molecule was previously described in the Journal of Medicinal Chemistry 2006 Vol 49, No 5, pp 1792-1799. This method allows production of a corresponding azide while keeping the anthracycline molecule intact.